Animal pruritus (itching) is a common affliction effecting domesticated animals and livestock alike. α-MSH and/or its derivatives have shown effectiveness in inflammatory conditions and the sequelac of those inflammatory conditions. See, Lipton, J. M., et al., Anti-inflammatory Influence of the Neuroimmunomodulator α-MSH, Immunol. Today 18, 140-145 (1997). Pruritus is a frequent element of inflammation. Any number of diseases or conditions can cause it. Everything from fleas to allergies can be the base cause but the result is same, i.e. excoriation (badly scratched skin), vesicular and papular rashes (rashes made up of varying sizes of blisters), erythema (reddening of the skin) hair loss, scaling, open lesions secondary to excoriation and opportunistic infection of open lesions.
Pruritus is the most common veterinary sign in animal dermatology. In humans, pruritus manifests as a symptom that most times a person can relate to a caregiver. In an animal, the pruritus presents as a sign in either a epicritic (localized) distribution or in a protopathic (poorly localized) distribution which is communicated to an owner via scratching, agitation, hair loss, or, sometimes, auto-inflicted wounds.
Pruritus is the result of chemical reactions occurring in the skin of the animal that result in nociceptor activation of afferent fibers in the nerves. Some of the chemicals mediators involved are prostaglandins, arachidonic acid, proteolytic enzymes, cytokines, histamine, serotonin, platelet activating factor, kallikrein, bradykinin, substance P and leukotrienes. A universal mediator to explain pruritus has not been found. See, Goldsmith, L. A. (Ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd ed. Oxford University Press. It has been asserted, on the basis of studies performed on humans, that proteolytic enzymes are the most important mediators of pruritus in dogs and cats. Clinical studies have suggested that histamine and leukotrienes are important in cats and dogs. See, Scott, D. W., Miller, W. H., Jr.: Nonsteroidal anti-inflammatory Agents in the Management of Canine Allergic Pruritus: J. S. Afr. Vet. Assoc. 64:52, 1993; Scott, D. W., Miller, W. H., Jr.: Medical Management of Allergic Pruritus in the Cat, with Emphasis on Feline Atopy: J. S. Afr. Vet. Assoc. 64:103: 1993. As these are the same chemicals affecting the inflammatory reaction, controlling inflammation is one way to ameliorate pruritus that results from the actions on the nerves of the various chemicals.
Those pruritic conditions that are the result of secondary sources, like fleas for example, are curable. Unfortunately, primary causes of pruritus, such as auto-immune diseases, are chronic and can not be cured. See, Columbia Animal Hospital School of Medicine, at <http://www.cah.com/medicine.html>. In this case the disease requires frequent or lifelong treatment. A well-tolerated treatment with minimal or no side effects would be a great advantage.
The causes, whether secondary or primary, of animal pruritus, are numerous. By far, allergies are the most common cause. Other common causes include, but are not limited to, hormonal hypersensitivities, food hypersensitivity, bacterial, fungal or parasitic hypersensitivity, auto-immune disorders and other glandular disorders.
Allergies are manifested as the result of numerous allergens. The most common is allergy to flea saliva. Certain animals become sensitized to components of flea saliva. Thereafter, each fleabite stimulates an allergic reaction that results in intense pruritus, erythema and papules. These changes can be localized or generalized, and are usually apparent around the base of the tail and spine, inner thighs and on the abdomen. This problem is affected by the seasons; as much because of the number of possible fleabites in different seasons as by the animal's natural response to different climate conditions. Further, the reaction is worse in older animals.
Because allergy to fleas is a hypersensitivity reaction and not simply a response to the number of bites, the severity of the pruritus and the skin changes are not necessarily proportional to the number of fleas. In other words, one fleabite on a highly sensitized animal may produce a severe reaction. See, Scott, Miller & Griffen, Muller & Kirk's Textbook of Animal Dermatology 5th Ed. W. B Saunders Company (1995). The inability to demonstrate fleas or flea dirt on the animal in no way precludes the diagnosis. A compound directed at both ridding the animal of fleas and alleviating that animal's reaction to its hypersensitivity would be beneficial.
Mange, a parasitic condition, is a veterinary problem similar to fleabite hypersensitivity. This common infection is result of either Sarcoptes Scabei or Demodex Canis. Untreated mange can result in loss of hair, erythema, agitation, flaking and crusting of the skin, and auto-mutilation. Treatment is usually effective but can be time consuming—several months in duration—and tedious, with multiple shampoos, dips, insecticides and clipping. An antipruritic addition to this therapy would make the long-term course more effective with limitation of auto-mutilation through increased comfort to the animal.
An additional and common cause of pruritus in animals is atopy. This is a generalized type of inhalant allergy. It is the second most common allergic skin disease in dogs. It also can be seen in cats but is noticed on a much less frequent basis. See, Cornell University College of Veterinary Medicine Newsletter, December 1999, <http://www.txk9cop.com/allergy.htm>. Further, this disease, which is believed to be the result of an autosomal recessive trait, shows varying penetration in different breeds of the same species.
The disease commonly starts by the third year of age. In the primary stages of the disorder, the pruritus is seasonal and is associated with only one or two seasons of the year. However, the pruritus becomes recalcitrant as the animal grows older and may last all year long. Glucocorticoid therapy has been the treatment of choice to control the pruritus and inflammation. Discussed below, steroids have many untoward side effects. Some of these side effects may be dangerous for the animal.
In the case of atopy, an anti-pruritic treatment may be needed while a search for the allergens and subsequent desensitization procedures are performed. Allergens that cause a more intense epicritic or protopathic reaction in the animal may be controlled in degree by variable dose related therapy. In this way, the graded treatment of the pruritus would not interfere with the differential diagnosis of allergens while making the duration of the diagnostic process more tolerable to the animal.
Many animals may suffer from food allergies. Additionally, the specific food the animal is allergic to may be one that animal has eaten for some time and has slowly developed a sensitivity. Large protein molecules often are the source of the food allergy. See, Dr. Roen's Weekly Column, at <http://www.roen.com/990913.html>.
These allergies manifest as dermatological problems and not as gastroenteric problems. For example, the great majority of dogs with food allergy have pruritus and lack any other dermatological changes or gastrointestinal disease whatsoever. Once the pruritus is traced to a food allergy, the veterinarian commences the search for the specific allergen. Again, once the allergen is found, the use of an anti-pruritic is helpful during the process of desensitization. This keeps the animal comfortable and avoids damage to the skin of the animal through excoriation.
Hormonal hypersensitivity is a rare condition in some animals causing severe pruritus. In this case, the animal is allergic to its own hormones. This is usually a “self-limiting” type of disorder, i.e. it runs a particular, though often not predictable, Commonly the disease appears during estrus (heat in dogs, for example). Because the pruritus disappears spontaneously when the estrus is over, treatment is only needed for that period of active pruritus. A treatment with little or no side effects would be a desired course.
Bacterial and fungal skin infections are another common cause of pruritus in animals. Staphylococcus sp., are the most common microorganisms found in the bacterial skin diseases. In fungal disease (commonly referred to as “ringworm”) Microsporum sp., and Trycophyton sp., are the most common fungal organisms. Candida albicans is yet another example of a fungus that infects animals and causes pruritus. Although these are all common to the flora of animal skin, they are also opportunistic pathogens capable of infecting the animal skin given the right conditions.
Antibiotic treatments, whether alone or in combination with fungicides or glucocorticoids, suffer many of the same deficiencies as glucocorticoid treatments. Glucocorticoid treatment tends to promote growth of microbes. Antibiotic sensitivities may further contribute to the pruritus the antibiotics are administered to treat. Antibiotic treatments are expensive and require animal supervision and strict compliance. In the commercial livestock context, antibiotics affect food and water consumption and voiding and may cause a loss of muscle mass.
As noted above, bacterial infection is one of the common sequelae of pruritus in that the animal may open a wound secondary to excoriation. Further, the bacterial infection may be the result of parasitism or general immune deficiency. A combination for treatment including antipruritic and/or antibacterial and antifungal properties would be beneficial to the animal suffering from bacterial or fungal based pruritus.
Treatments for the various causes of pruritus are as varied as the causes of the pruritus. The range of treatments varies in relation to the severity and etiology of the disorder causing the pruritus. For example, cold water can produce temporary relief in simple epicritic-type pruritus. Longer relief can be obtained by using additives with the water. Common additives include different varieties of oatmeal-based shampoos or cream rinses, and Domeboro® solution or Aveeno® used as rinses. Certain other shampoo treatments, depending on the etiology of the pruritus, contain an antibacterial agent, salicylic acid, tar and fatty acids. These methods, as mentioned, are only temporary and not well suited for compliance. Still, therapeutic shampoos remain an important part of a number of treatment protocols. See, Mike Richards, DVM at, <http://www.vetinfo.com/dallergy.html> (Jan. 13, 2001).
As the pruritus becomes more severe, or is the result of a more complicated origin, the treatments become more complicated. When treatments become more medicinal or invasive the potential for complications and side effects naturally increase. One medicinal treatment is to use either prescription or over-the-counter antihistamines. Often the antihistamines are combined with fatty acid inhibitors. Used alone, about 15 to 25% of dogs will respond to antihistamines and in combination with fatty acid inhibitors show only an efficacy of up to 40%. Most animals, while showing some level of reduction in scratching behavior, show lethargy or drowsiness and drying of mucous membranes. Some animals are known to show paradoxical agitation with antihistamines. See, Id.
Fatty acid derivatives that compete with arachadonic acid (a known trigger for pruritus) and replace it with an inactive competitor are useful, in high doses, against certain types of pruritus. Unfortunately, these medicines must be used for months and are only available through a veterinarian. Additionally, they are very expensive.
In spite of the tediousness, time consumption, and expense of the above medications and treatments, they are preferable to injection therapy or the next most common line of treatment which is glucocorticoid therapy.
Oral or parenteral glucocorticoids are often used in complicated or uncontrolled pruritus. Although the medications are often effective, they have many unfortunate side effects in long term use. They can: increase thirst resulting in increased voiding; increase appetite, resulting in difficulty in weight control; decrease bone density; increased occurrences and chance of pancreatitis; cause immunosuppression via lymphocyte depression with increased risk of secondary infection; induce Cushing's disease; hair loss; variations in hormonal control of water balance; and, muscle weakness. These potential complications require frequent visits to or by the veterinarian to monitor the animal on steroid therapy. Further, topical steroid use has multiple drawbacks. For example, topical steroid use for as little as two weeks can cause: 1) telangiectasia (dilation of capillaries and sometimes of terminal arteries producing an angioma of macular appearance, or hyperemic spot); 2) skin atrophy or thinning of the skin; and 3), mask an infection or suppress the host response to invasion by opportunistic pathogens.
This latter point, whether from intralesional injection, oral, parenteral or topical use, is of great importance in any dermatological disorder that may result in an open lesion. Open lesions are a notoriously favorable environment for opportunistic infection. The warmth, blood supply, pH, and necrotic tissue are all conducive to bacterial or fungal colonization. Using a steroid in this environment may slow the response to an infection and thereby mask commonly observed and treated signs of an infection; namely, purulence or pus. Thus, a simple infection in the presence of a topical steroid can be masked to the point of serious infection and sepsis.
Reduced killing of pathogens is a detrimental consequence of therapy with anti-inflammatory drugs. In addition to its potent anti-inflammatory effects, α-MSH and/or its derivatives have anti-microbial efficacy as well. α-MSH and/or its derivatives inhibit common skin pathogens, i.e. Staphylococcus Aureus and Candida Albicans, show bactericidal and fungicidal properties, respectively. See, Cutull, Cristiani, Lipton and Catania, Antimicrobial Effects of α MSH Peptides, Journal of Leukocyte Biology, Volume 67, February 2000.
It follows that the use of a preparation that could offer all the benefits of steroid preparations, shampoos and other soothing agents, but without the attendant side effects and with a more facile tolerance and compliance, will be a great addition to the available avenues of treatment of these disorders.
Based on the foregoing, a preferred composition for the treatment of pruritus would be anti-inflammatory without causing immunosuppression. A preferred composition would also have antibiotic and antifungal properties with little to no immuno-cross-reactivity i.e., it would be hypoallergenic. A preferred composition would also be therapeutically effective at low concentrations and have little effect on appetite, muscle mass, and water balance so that it would be commercially practicable to the livestock industry.